6H-dibenz[b,e][1,4]oxathiepin compounds

ABSTRACT

Novel 6H-dibenz[b,e][1,4]oxathiepin derivatives of the formulae I and Ia are employed in the treatment and control of allergic conditions such as allergic asthma. ##STR1##

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 817,373, filed Jan. 9, 1986,now U.S. Pat. No. 4,699,917 which is a continuation-in-part of Ser. No.238,097 filed Feb. 25, 1981, now abandoned, which was a continuation ofSer. No. 930,103, filed Aug. 1, 1978, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to new and useful compositions of matterclassifiable in the field of organic chemistry as dibenzoxathiepins.More particularly, the instant invention relates to a novel group of6H-dibenz[b,e][1,4]oxathiepins; to metnods of preparing such compounds;and to the method of employing them in the treatment and control ofallergic conditions such as asthma.

SUMMARY OF THE INVENTION

In its composition aspect, therefore, the instant invention may bedescribed as residing in the concept of isomeric6H-dibenz[b,e][1,4]oxathiepins characterized by having the followingstructural formulae: ##STR2## wherein Z is a member selected from thegroup consisting of thio, sulfinyl or sulfonyl; R₂ and R₃ are the sameor different and are members selected from the group consisting ofhydrogen, halogen, nitro, loweralkyl, amino, N-loweralkylamino,N,N-diloweralkylamino, loweralkanoyl, hydroxy, loweralkoxy,loweralkylthio, trifluoromethylthio, loweralkylsulfinyl,loweralkylsulfonyl or trifluoromethyl; and R₁ is a member selected fromthe group consisting of 5-tetrazolyl, 5-tetrazolylmethyl,3-hydroxy-1,2,5-thiadiazol-4-yl, 4-hydroxy-Δ³ -pyrroline-3-yl-2,5-dioneor ##STR3## wherein n is an integer from 0-4 and R₄ is a member selectedfrom the group consisting of hydroxy, loweralkoxy,N,N-diloweralkylaminoloweralkoxy, hydroxyloweralkoxy, arboxyloweralkoxy,amino, N-loweralkylamino, N,N-diloweralkylamino,loweralkylsulfonylamino, carboxyloweralkylamino,carboxamidoloweralkylamino, 2-imino-3-methylthiazolidine,loweracyloxyloweralkoxy or (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy,and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION

As used herein, the term, halogen, includes chlorine, bromine, iodineand fluorine. The terms, loweralkyl and loweralkoxy, wherever employed,include straight and branched chain alkyl and alkoxy groups having 1 to4 carbon atoms in the alkyl or alkoxy moiety such as, for example,methyl, ethyl, isopropyl, butyl, ethoxy, propoxy and isobutoxy. Theterm, loweralkanoyl, includes straight and branched chain alkanoylgroups of 1 to 4 carbon atoms including, for example, formyl, acetyl,propanoyl and butyryl.

The instant invention is based upon applicants' discovery that theoxathiepins of formula I and Ia, above, markedly antagonize the actionsof contractile prostaglandins such as PGF₂α, PGG₂, PGH₂ and TXA₂. Theuse of the oxathiepins of this invention, which act as prostaglandinantagonists, and biosynthesis inhibitors, offers a new approach totherapy in a variety of allergic conditions such as allergic asthmawhere excessive contractile activity of prostaglandins and prostaglandinbiosynthetic intermediates occur. It is well known, for example, thatprostaglandins such as PGF₂α, PGG₂, TXA₂ and PGH₂ are potentcontractants of bronchial muscle and that human asthmatics areespecially sensitive to the bronchial constricting action of PGF₂α. Theantagonizing action of the oxathiepins of this invention against theconstricting actions of contractile prostaglandins has been confirmingin vitro and in vivo using standard pharmacological techniques. It iscontemplated, therefore, that the oxathiepins of this invention will beemployed in dosage unit form as the essential active ingredient inpharmaceutical formulations intended for the treatment and control ofallergic conditions such as asthma in humans and warm blooded animals.

The novel oxathiepins of this invention, conveniently, are prepared fromthe 2-(or 9-)cyano intermediates having the following structuralformulae: ##STR4## wherein R₂ and R₃ are as previously defined. These2-(or 9-)cyano-6H-dibenz[b,e][1,4]oxathiepin intermediates arethemselves readily prepared from well known starting materials which areeither available commercially or may be prepared by conventionaltechniques already fully described in the chemical literature.

Thus, 2-cyano-6H-dibenz[b,e][1,4]oxathiepin (II) may be preparedaccording to the following general reaction scheme: ##STR5## wherein R₂and R₃ are as previously defined, by treating an appropriatelysubstituted (R₂ and/or R₃) o-iodobenzoic acid with o-methoxythiophenolin the presence of copper powder and aqueous potassium hydroxide inorder to obtain the corresponding 2-(o-methoxyphenylthio)benzoic acid.The reaction is carried out at reflux and usually requires 2 to 5 hoursfor completion. Upon recovery, the acid product may be converted intothe corresponding lower alkanol ester by refluxing with a lower alkanolin the presence of a strong acid such as sulfuric acid, hydrochloricacid, trifluoroacetic acid and the like. The ester product then istreated with dichloromethyl methyl ether in the presence of titaniumtetrachloride to form the corresponding3-(o-carboloweralkoxyphenylthio)-4-methoxybenzaldehyde which then isdemethylated with hydrogen bromide in glacial acetic acid to form thecorresponding 3-(o-carboxyphenylthio)-4-hydroxybenzaldehyde. Thealdehyde so produced then is treated with hydroxylamine hydrochloride inthe presence of sodium formate and formic acid to form the corresponding3-(o-carboxyphenylthio)-4-hydroxybenzonitrile which is treated withdichclohexylcarbodimide (DCC) to form the correpsonding2-cyano-6H-6-oxo-dibenz[b,e][1,4]oxathiepin. The 2-cyano-oxatheipinproduct then is treated with an alkali metal borohydride to form thecorresponding 3-(o-hydroxymethylphenylthio)-4-hydroxybenzonitrile whichis reacted with dichclohexylcarbodiimide to form the desired2-cyano-6H-dibenz[b,e][1,4oxthiepin of formula II.

9-Cyano-6H-dibenz[b,e][1,4]thiepin (IIa) may be prepared according tothe following general reaction scheme: ##STR6## wherein R₂ anc R₃ are aspreviously defined, by treating an appropriately substituted (R₂ and/orR₃) o-aminothiophenol with 2-chloro-4-nitrobenzoic acid in the presenceof cuprous oxide to form the corresponding2-(o-aminophenylthio)-4-nitrobenzoic acid which then is suspended inwater, acidified with sulfuric acid, treated with sodium nitritefollowed by sodium fluoroborate to obtain the diazonium fluoroboratewhich is heated in 50% sulfuric acid to obtain the corresponding2-(o-hydroxyphenylthio)-4-nitrobenzoic acid. The acid product is treatedwith borane in tetrahydrofuran to form the corresponding2-(o-hydroxyphenylthio)-4-nitrobenzyl alcohol which is cyclized in thepresence of dicyclohexylcarbodiimide (DCC) to form the corresponding9-nitro-6H-dibenz[b,e][1,4]oxathiepin. The nitro group then is reducedto the 9-amino compound with stannous chloride and the amine is treatedwith sodium nitrite followed by a mixture of cuprous cyanide andpotassium cyanide to obtain the desired9-cyano-6H-dibenz[b,e][1,4]oxathiepin of formula IIa.

The novel oxathiepins of the instant invention wherein the substituentat the 2-(or 9-)position is carboxy are prepared by refluxing the 2-(or9-)cyano intermediates of formula II or IIa in a mixture of ethanol andaqueous sodium hydroxide. The reaction usually requires from 2 to 6hours for completion and the desired 6H-dibenz[b,e][1,4]oxathiepin-2-(or9-)carboxylic acid of formula III or IIIa is recovered from the reactionmixture upon acidification. ##STR7##

The novel oxathiepins of this invention wherein the substituent at the2-(or 9-)position is 5-tetrazolyl also are prepared from the 2-(or9-)cyano intermediates of formula II or IIa. The nitrile is heated in amixture of sodium azide and ammonium chloride in a suitable organicsolvent such as dimethylformamide. Conveniently, the reaction is carriedout at reflux and usually requires 4 to 12 hours for completion. Afterdilution with excess sodium carbonate and extraction with ethyl acetate,the aqueous phase is acidified to obtain the desired 2-(or9-)(1H-tetrazol-5-yl)-6H-dibenz[b,e][1,4] oxathiepin of formula IV orIVa. ##STR8##

Formation of the 11-oxide or the 11,11-dioxide groups (e.g., preparationof the sulfinyl or sulfonyl compounds of the instant invention)conveniently is achieved by controlled oxidation techniques. Thus, forexample, the carboxylic acid derivatives of formula III or IIIa may beoxidized with hydrogen peroxide in the presence of an acidic solventsuch as acetic acid or with organic peroxides such as peroxy acids, forexample, m-chloroperbenzoic acid and the like, in a stepwise fashion toform the corresponding sulfinyl derivative, formula V or Va, andsulfonyl derivative, formula VI or VIa, by controlling the molar ratioof oxidant to reductant. The molar ratio determines the oxidation levelof the sulfur in the product. A 1:1 molar ratio, for example, resultslargely in the production of the sulfinyl derivative whereas a 2 to 3molar excess of oxidant results in a yield predominately comprising thesulfonyl derivatives. ##STR9##

The oxidation technique described above is generally applicable topreparation of any of the sulfinyl or sulfonyl compounds of thisinvention from the corresponding oxathiepin. Thus, for example, the5-tetrazolyl compounds of formula IV or IVa may be subjected tocontrolled oxidation in order to obtain the corresponding sulfinyl andsulfonyl compounds.

Alternatively, the 2-(or 9-)cyano intermediates of formula II or IIa maybe oxidized as described above to produce the corresponding sulfinyl orsulfonyl intermediate. These intermediates then may be converted to thecorresponding 2-(or 9-)carboxylic acid or 5-tetrazolyl compounds by themethods already described.

In addition to their therapeutic properties as noted above, the 2-(or9-)carboxylic acid derivatives of this invention serve as valuableintermediates in the preparation of other variously substituted andtherapeutically useful 6H-dibenz[b,e][1,4]oxathiepins of formula I andIa. Thus, the 2-(or 9-)carboxylic acid of formula III or IIIa may beconverted readily into the corresponding acid halide, preferably theacid chloride, by treating the carboxylic acid with a thionyl halide,preferably thionyl chloroide. The resulting 2-(or9-)halocarbonyl-6H-dibenz[b,e][1,4]-oxathiepin (i.e., the 2-(or9-)chlorocarbonyl compounds of formula VII or VIIa) then may be treatedwith various well-known reagents to form desired ester and amidederivatives. ##STR10##

Thus, for example, the chlorocarbonyl compounds of formula VII and VIIamay be treated:

(a) with a loweralkano such as, for example, methanol, ethanol,2-propanol, butanol and 2-butanol, to form the corresponding (R=)loweralkyl esters, VIII and VIIIa: ##STR11##

(b) with ammonia to form the corresponding carboxamides, X and IXa:##STR12##

(c) with an N-loweralkylamine such as, for example, methylamine,ethylamine, propylamine, isopropylamine and butylamine, or anN,N-diloweralkylamine such as, for example, dimethylamine, diethylamine,dipropylamine and dibutylamine, to form the coresponding (R₁ =)N-loweralkylcarboxammide X or Xa, or N,N-diloweralkylcarboxamide, XI orXIa: ##STR13##

(d) with a loweralkylsulphonamide such as, for example,methanesulphonamide, ethanesulphonamide, propanesulphonamide andbutanesulphonamide, to form the corresponding (R₁ =)N-loweralkylsulfonylcarboxamide, XII or XIIa: ##STR14##

(e) with 2-imino-3-methylthiazollidine to form the corresponding (R₁ =)(3-methyl-2-thiazolidinylidene) carboxmide, XIII and XIIIa: ##STR15##

(f) with a loweralkyldiol such as, for example ethylene glycol,trimethylene glycol and 1,4-butanediol, to form the corresponding (R₁ =)hydroxyloweralkylester, XIV and XIVa: ##STR16##

(g) with an N,N-diloweralkylaminoloweralkanol such as, for example,N,N-dimethylethanolamine, N,N-diethylethanolamine,3-N,N-dimethylaminopropan-1-ol and 4-N,N-diethylaminobutan-1-ol, to formthe corresponding (R₁ =) N,N-diloweralkylaminoloweralkyl ester, XV andXVa: ##STR17##

(h) with an amino acid such as, for example, glycine, alanine andvaline, to form the corresponding (R₁ =) N-carboxyloweralkylcarboxamide,XVI and XVIa: ##STR18##

(i) with an alkali metal salt of a hydroxyloweralkanoic acid such as,for example, hydroxyacetic acid, 3-hydroxybutyric acid andβ-hydroxypropionic acid, to form the corresponding (R₁ =)Carboxyloweralkyl ester, XVII and XVIIa: ##STR19##

Where the corresponding sulfinyl or sulfonyl derivatives are desired,the corresponding 11-oxide or 11,11-dioxide 2-(or 9-)carboxylic acid,e.g. a compound of formula V, Va, VI or VIa, may be substituted forstarting material III or IIIa in the foregoing reaction sequence.Alternatively, it will be clear to those skilled in the art that theproduct esters and amides obtained in the foregoing reaction sequencemay be oxidized by the techniques already described to obtain thecorresponding sulfinyl or sulfonyl derivatives.

Those oxathiepins of this invention wherein the substituent at the 2-(or9-)position is 3-hydroxy-1,2,5-thiadiazol-4-yl are prepared by refluxingthe 2-(or 9-)cyano intermediate in formic acid in the presence of Raneynickel alloy for 1 to 2 hours in order to obtain the corresponding6H-dibenz[b,e][1,4]oxathiepin-2-(or 9-)carboxaldehyde. The aldehydeproduct then is converted into the corresponding 2-(or9-)2-aminoacetonitrile by treatment with sodium cyanide in an alcoholicsolvent saturated with ammonia and in the presence of ammonium chlorideand ammonium hydroxide. The reaction usually is conducted at roomtemperature and requires from 8 to 16 hours to completion. Theaminoacetonitrile so produced is treated with concentrated hydrochloricacid at room temperature for 20 to 45 minutes in order to obtain thecorresponding 2-(or 9-)(2-aminoacetamide) which then is treated withsulfur monochloride in dimethylformamide to obtain the desired (R₁ =)2-(or 9-)(3-hydroxy-1,2,5-thiadiazol-4-yl) 6H-dibenz[b,e][1,4]oxathiepinof formula XVIII, XVIIIa. This reaction sequence is illustrated in thefollowing diagram, it being understood that position of the3-hydroxy-1,2,5-thiadiazol-4-yl substituent in the final product dependsupon the selection of the appropriate 2-(or 9-)cyano starting material.##STR20##

The novel oxathiepins of this derivative wherein the R₁ substituent atthe 2-(or 9-) position is 4-hydroxy-Δ³ -pyrroline-3-yl-2,5-dione areprepared from the appropriately substituted 2-(or 9-)carboxylic acid oyreducing the acid to the corresponding alcohol with borane intetrahydrofuran. The reaction conveniently is carried out at roomtemperature under an inert atmosphere and usually requires 2 to 4 hoursfor completion. The alcohol then is brominated with phosphoroustribromide and the bromomethyl so produced is treated with sodiumcyanide to form the corresponding 2-(or 9-)cyanomethyl derivative. Thesereactions may be carried out at room temperature and usually requirefrom 1 to 3 hours for completion. The cyanomethyl intermediate then ishydrolyzed to the corresponding acetic acid which is treated withthionyl chloride followed by ammonia to form the corresponding 2-(or9-)acetamide derivative by techniques already described. The acetamidethen is treated with diethyl oxalate in dimethylformamide in thepresence of potassium t-butoxide to form the desired (R₁ =) 2-(or9-)(4-hydroxy-Δ³ -pyrrolin-3-yl-2,5-dione)-6H-dibenz[b,e][1,4]oxathiepinof formula XIX and XIXa.

This reaction sequence is illustrated in the diagram below, it againbeing understood that the position of the hydroxypyrrolinedione in thefinal product depends upon the selection of the 2-(or 9-) carboxylicacid starting material. ##STR21## Where corresponding sulfinyl orsulfonyl derivatives are desired, the products of both reaction schemesdescribed above may be oxdized by the techniques already described.

It will be noted that the reaction sequence described above afford asnot only oxathiepins of this invention wherein the substituents at the2-(or 9-) position is hydroxy-Δ³ -pyrroline-3-yl-2,5-dione, but, inSteps A-D, lead also to the preparation of those oxathiepins of thisinvention wherein the substituent at the 2-(or 9-) position is aloweralkanoic acid (i.e., compounds of formula I and Ia, wherein R₁ is##STR22## n is an integer between 1 and 4 and R₄ is hydroxy). Thus,Steps A-D, as described above, starting with the appropriatelysubstituted 2-(or 9-)carboxylic acid, through reduction, bromination,cyanization and oxidation afford the corresponding 2-(or 9-)acetic acidderivative. Quite obviously, the described reduction, bromination,cyanization and oxidation sequence can be repeated, employing the 2-(or9-) acetic acid derivative as starting material, in order to obtain thecorresponding propionic acid derivative which, in turn, can be employedas starting material for preparing the corresponding butyric acidderivative. In this manner, any desired 2-(or 9-) loweralkanoic acidderivative of the instant invention readily is prepared. Correspondingsulfinyl or sulfonyl derivatives are prepared by the oxidationtechniques previously described.

The 2-(or 9-) cyano loweralkyl intermediates obtained from Steps A-C inthe reaction sequence described above also serve as intermediates in thepreparation of other therapeutically active oxathiepins of formula I orIa. Thus, for example, an appropriately substituted 2-(or 9-)cyanomethyl-6H-dibenz[b,e][1,4]oxathiepin may be treated with sodiumazide and ammonium chloride by techniques previously described to formthe corresponding 2-(or 9-)(1H-tetrazol-5-yl-methyl)-6H-dibenz[b,e][1,4]oxanthiepin and the product, if desired, can be oxidized to form thecorresponding sulfinyl or sulfonyl derivative.

The halogen substituted 6H-dibenz[b,e][1,4] thiepin derivatives (R₂ orR₃ =F, Cl, Br or I) are prepared as shown in the following reactionsequence which illustrates the preparation of 8-(or 9-)fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid of formula XX andXXa and the corresponding -11,11-dioxide XXI and XXIa. ##STR23##

2-Amino-5-(or 4-) nitrobenzoic acid is converted into the disulfidecarboxylic acid by reaction with (1) sodium nitrite and sulfuric acid;(2) potassium xanthogenate; and (3) sodium carbonate/water.

The disulfide is converted to 2-mercapto-5-(or 4-)nitrobenzyl alcohol byreductive cleavage using diborane.

Reaction of the mercaptonitrobenzyl alcohol with4-hydroxy-3-iodo-benzoic acid in the presence ofN-methyl-2-pyrrolidinone affords 3-(2-hydroxymethyl-4(or5)-nitrophenylthio)-4-hydroxybenzoic acid.

Esterification of the benzoic acid is accomplished with methanol andsulfuric acid. Ring closure of the diol using diethyl azodicarboxylateand triphenylphosphine affords methyl 8- (or 9-)nitro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate.

The 8-(or 9-) nitro group is then reduced using stannous chloride toafford the 8-(or 9-) amino compound. Reaction of the 8-(or 9-) aminocompound with sodium nitrite and hydrogen tetrafluoroborate affords thediazonium tetrafluoroborate salt. Heating this salt affords the 8-(or9-) fluoro compound.

Hydrolysis of the methyl 8-(or 9-)fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate with (1) sodiumhydroxide/water; and (2) hydrochloric acid affords the 8- (or 9-)fluoro-6H-dibenz[b,e][1,4]oxathiepin- 2-carboxylic acid. Treatment ofthe carboxylic acid with hydrogen peroxide/acetic acid yields thecompound 8- (or 9-) fluoro-6H-dibenz[b,e][1,4]oxathipin-2-carboxylicacid-11,11-dioxide.

As noted above, pharmaceutically acceptable salts of the noveloxathiepins also are included with the scope of this invention. Theterm, pharmaceutically acceptable salts, is intended to include saltsderived from pharmaceutically acceptable non-toxic acids and bases suchas, for example, ammonium salts, alkali metal salts such as sodium andpotassium salts, alkaline earth metal salts such as magnesium andcalcium salts, salts of organic bases such as amine salts derived frommono-, di- and triloweralkyl or hydroxyloweralkanyl amines such astrimethylamine, dimethylamine and triethanolamine, salts derived fromheterocyclic amines such as piperidine, 1-methylpiperazine, piperazineand morpholine, and salts derived from pharmaceutically acceptable acidssuch as hydrochloric acid, sulfuric acid, tartaric acid and propionicacid.

It will be noted by the skilled artisan that many of the carboxylic acidderivatives encompassed by formulae I and Ia will serve as pro-drugs ofthe active carboxylate form in vivo. Several of these derivatives alsopossess bioactivity in their own right. For a general discussion ofpro-drugs see A. A. Sinkula, Ann. Rpts. Med. Chem. 10 306-316 (1975),wherein the utility of pro-drug forms, for example esters, amides andamino acid amide derivatives of carboxylic acids are shown to provideuseful means of administering the drug.

The oxathiepins of formula I and Ia are useful in the treatment andprophylaxis of human or warm-blooded animal disease conditions whereexcessive undesirable contractile activity of prostaglandins, such asPGF₂α, or prostaglandin biosynthetic intermediates contribute. Inparticular, they are of value in the treatment and control of allergicconditions such as asthma.

The magnitude of a prophylactic or therapeutic dose of compound offormula I and Ia will, of course, vary with the nature and the severityof the condition to be treated and with the particular compound offormula I and Ia and its route of administration. In general, the doserange lies within the range of 0.2 mg to 100 mg per kg body weight perday.

The pharmaceutical compositions of the present invention comprise acompound of formula I and Ia as an active ingredient, and may alsocontain pharmaceutically acceptable carrier and optionally othertherapeutic ingredients. The compositions include compositions suitablefor oral, rectal, opthalmic, pulmonary, nasal, dermal, topical orparenteral (including subcutaneous, intramuscular and intravenous)administration, although the most suitable route in any given case willdepend on the nature and severity of the condition being treated and onthe nature of the active ingredient. They may be conveniently presentedin unit dosage form and prepared by any of the methods well known in theart of pharmacy.

For use where a composition for intravenous administration is employed,a suitable dosage range is from 0.2 to 10 mg (preferably 1 to 8 mg) of acompound of formula I and Ia per kg of body weight per day and in thecase where an oral composition is employed a suitable dosage range isabout, e.g., 1 to 50 mg of a compound of formula I and Ia per kg of bodyweight per day, preferably from 5 to 40 mg/kg.

Pharmaceutical compositions of the present invention suitable for oraladministration and by inhalation in the case of asthma therapy may bepresented as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active ingredient; as a powderor granules; or as a solution or a suspension in an aqueous liquid, anon-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquidemulsion. Such compositions may be prepared by any of the methods ofpharmacy but all methods include the step of bringing into associationthe active ingredient with the carrier which constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product into the desired presentation. Forexample, a tablet may be prepared by compression or moulding, optionallywith one or more accessory ingredients. Compressed tablets may beprepared by compressing in a suitable machine, the active ingredient ina free-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine, a mixture of powdered compound moistened with an inert liquiddiluent. Desirably, each tablet contains from 50 mg to 500 mg of theactive ingredient and each cachet or capsule contains from 50 mg to 500mg of the active ingredient.

Tne best mode contemplated by applicants for carrying out theirinvention is illustrated in the following working examples. Nolimitation, however, is intended except as set forth in the appendedclaims.

EXAMPLE 1 9-Cyano-6H-dibenz[b,e][1,4]oxathiepin Step A2-(o-Aminophenylthio)-4-nitrobenzoic acid

Heat a mixture of 466 g (3.72 moles) of 2-aminothiophenol, 250 g (1.24moles) of 2-chloro4-nitrobenzoic acid, 1.25 liters of quinoline, 192 g(1.34 moles) of cuprous oxide and 125 ml of pyridine in an oil bath at160°-170° C. with mechanical stirring for 90 minutes. Cool the mixtureto room temperature and add 1.87 liters of concentrated hydrochloricacid followed by 625 ml of water. Separate the precipitate and wash wellwith water. Extract the washed precipitate into boiling methanol andfilter. Treat the hot filtrate with charcoal, filter and strip todryness. Dissolve the residue in aqueous sodium hydroxide, filter andtreat with charcoal. Acidify the filtrate and separate the precipitate.(Yield: 38 g).

Additional Crop: Take up the insoluble residue from the basic extractioninto water, filter through Celite and acidify. Separate the precipitateand dissolve in ethyl acetate. Treat with charcoal, filter and strip todryness. (Yield: 23 g).

Step B 2-(o-Hydroxyphenylthio)-4-nitrobenzoic acid

Suspend 10.15 g (35 mmoles) of the amino acid of Step A in 75 ml ofwater and add 4 ml concentrated sulfuric acid (7.36 g, 75 mmoles, 140meq.). Cool the mixture in an ice-bath and add 3.657 g (53 mmoles) ofsodium nitrite in portions at 0°-5° C. Stir the suspension in the coldfor 20 minutes. Add 10 g (91 mmoles) of sodium fluoroborate and stir foran additional 20 minutes. Separate the precipitated crude diazoniumfluoroborate, suspend tne precipitate in 250 ml of 50% sulfuric acid andheat in an oil bath at 90°-100° C. for 45 minutes. Cool the mixture andseparate the precipitate. (Yield: 7.76 g).

Step C 2-(o-Hydroxyphenylthio)-4-nitrobenzyl alcohol

Dissolve 42 g (0.144 mole) of the acid of Step B in 575 ml oftetrahydrofuran and add dropwise 275 ml of borane (0.275 mole BH₃) intetrahydrofuran under a nitrogen atmosphere at room temperature. Stir atroom temperature overnight. Slowly add excess water and concentrate toremove the tetrahydrofuran. Extract into ethyl acetate and add 120 g ofsilica gel to the ethyl acetate solution. Place the mixture atop acolumn of 1500 g of silica gel and elute with 20% ethyl acetate/benzeneto obtain the pure diol. (m.p. 131°-133° C.).

Step D 9-Nitro-6H-dibenz[b,e][1,4]oxathiepin

Stir 4.5 g of the diol of Step C and 17.1 g (5 molar equivalents) ofdicyclohexylcarbodiimide together at 110°-115° C. for 4-5 hours. Coolthe mixture, dissolve in 250 ml of tetrahydrofuran and filter. Addsilica gel to the filtrate and strip to dryness. Place the residue atopa column of 310 g of silica gel and elute with 50:50 benzene/hexane.Strip to dryness to obtain the title product. (m.p. 112°-113° C.).

Step E 9-Amino-6H-dibenz[b,e][1,4]oxathiepin

Dissolve 7.92 g of the nitro compound of Step D in 150 ml oftetrahydrofuran and add 50 ml of concentrated hydrochloric acid. Placethe mixture in a cold water bath and add 22.7 g (3 molarequivalents+10%) of stannous chloride dihydrate in portions. Stir atroom temperature for 51/2 hours. Dilute the reaction mixture with water,basify with 40% aqueous sodium hydroxide and extract with ethyl acetate.Wash the organics with water, dry and strip to dryness. (Yield: 7.22 gcrude amine.)

Step F 9-Cyano-6H-dibenz[b,e][1,4]oxathiepin

Suspend 1.55 g (6.77 mmoles) of the amine of Step E in 36 ml of 1Nhydrochloric acid and cool the mixture in an ice bath. Add slowly asolution of 502 mg (7.28 mmoles) of sodium nitrite in 10 ml of water,keeping the temperature at 0°-5° C. Stir the mixture in the cold for 15minutes. Neutralize to pH 7 with aqueous sodium carbonate solution. Addthe mixture slowly to a cooled mixture of 1.37 g (15.3 mmoles) ofcuprous cyanide and 2.0 g (30.8 mmoles) of potassium cyanide in 50 ml ofwater at 0°-5° C. Recover the precipitate by filtration and wash wellwith water. Dissolve the precipitate in tetrahydrofuran, add silica geland evaporate the tetrahydrofuran. Place the residue atop a silica gelcolumn and elute with 50:50 benzene/hexane. Remove the solvent to obtainthe title product. (m.p. 136°-137° C.).

EXAMPLE 2 9-Cyano-6H-dibenz[b,e][1,4]oxathiepin-11,11-dioxide

Dissolve 850 mg (3.56 mmole) of the9-cyano-6H-dibenz[b,e][1,4]oxathiepin of Example 1 in 50 ml of methylenechloride. Add 2.3 g (11.3 mmole) of 85% m-chloroperbenzoic acid and stirat room temperature for 2 hours. Add excess calcium hydroxide andcontinue stirring for a few minutes. Filter the reaction mixture throughcelite and strip the filtrate to dryness. Chromatograph the residue onsilica gel eluting with 25% ethyl acetate in benzene to obtain the titleproduct. (m.p. 177°-179° C.).

EXAMPLE 3 6H-Dibenz[b,e][1,4]oxathiepin-9-carboxylic acid-11,11-dioxide

Reflux 435 mg of the nitrile of Example 2 in a mixture of 20 ml of 20%aqueous sodium hydroxide and 20 ml of ethanol for 21/2 hours and cool toroom temperature. Dilute the reaction mixture with water and remove mostof the ethanol by evaporation under reduced pressure. Extract theaqueous residue with ethyl acetate. Acidify the aqueous solution, afterevaporation of residual ethyl acetate, and separate the precipitate byfiltration to obtain the title product. (m.p. 262°-265° C.).

EXAMPLE 49-(1H-Tetrazol-5-yl)-6H-dibenz[b,e][1,4]oxathiepin-11,11-dioxide

Heat together 435 mg (1.61 mmole) of the nitrile of Example 2, 156 mg(2.4 mmole) of sodium azide and 161 mg (3 mmole) of ammonium chloride in10 ml of dimethylformamide at 135° C. for 6 hours. Cool the reactionmixture to room temperature, dilute with water and excess aqueous sodiumcarbonate solution and extract with ethyl acetate. Acidify and extractthe separated solid with ethyl acetate or triturate in ether. Filter anddissolve the product in 40 ml of hot methanol. Filter and concentratethe filtrate to 15 ml. Cool and scratch to induce crystallization. Dryunder vacuum at 130° C. to obtain the title product. (m.p. dec. 225°C.).

EXAMPLE 5 6H-Dibenzo[b,e][1,4]oxathiepin-9-carboxylic acid

Reflux 800 mg of the nitrile of Example 1 in a mixture of 25 ml of 20%sodium hydroxide and 25 ml of ethanol for 3 hours. Cool the reactionmixture to room temperature and remove most of the ethanol byevaporation under reduced pressure. Dissolve the precipitated sodiumsalt by diluting with water and warming. Extract with ethyl acetate andacidify the aqueous phase. Separate the precipitate by filtration toobtain the title product. (m.p. 241°-243° C.).

EXAMPLE 6 6H-Dibenz[b,e][1,4]oxathiepin-9-carboxylic acid-11-oxide

Dissolve with warming 380 mg of the carboxylic acid of Example 5 in 38ml of glacial acetic acid. Place the reaction mixture in an oil bath at40° C. and, after equilibration, add 1.5 ml of 30% hydrogen peroxide.Stir the mixture at 40° C. for 31/2 hours until solution clears. Dilutewith 300 ml of water and separate the precipitate by filtration toobtain the title product (m.p. 242°-245° C.).

EXAMPLE 7 9-(1H-Tetrazol-5-yl)-6H-dibenz[b,e][1,4]oxathiepin

Heat a mixture of 800 mg (3.35 mmole) of the nitrile of Example 1, 293mg (4.5 mmole) of sodium azide and 265 mg (4.95 mmole) of ammoniumchloride in 25 ml of dimethylformamide at 130°-135° C. for 6 hours.Dilute the mixture with water and excess sodium carbonate. Extract withethyl acetate. Acidify the aqueous phase and separate the precipitate byfiltration to obtain the title product. (m.p. melts with dec. 195°-200°C.).

EXAMPLE 8 9-(1H-Tetrazol-5-yl)-6H-dibenz[b,e][1,4]oxathiepin-11-oxide

Dissolve with warming 500 mg (1.77 mmole) of the tetrazolyl compound ofExample 7 in 50 ml of glacial acetic acid. Place the reaction mixture inan oil bath at 45° C. and, after equilibration, add 2 ml of 30% hydrogenperoxide. Stir at 45° C. for several hours until the sulfoxidecrystallizes out. (m.p. dec. 292°-295° C.).

EXAMPLE 9 2-Cyano-6H-dibenz[b,e][1,4]oxathiepin Step A2-(o-Methoxyphenylthio) benzoic acid

Stir under reflux for 3 hours a mixture of 70 g (0.5 mole) ofo-methoxythiophenol, 120.5 g (0.486 mole) of o-iodobenzoic acid 81.7 g(1.46 mole) of potassium hydroxide, 85 g (1.34 mole) of copper powderand 800 ml of water. Filter the reaction mixture hot and again filterthe filtrate through celite. Acidify the filtrate with concentratedhydrochloric acid. Separate the precipitate, wash well with water anddry in vacuo at 70° C. to obtain the title product. (m.p. 198°-200° C.)

Step B Methyl 2-(o-methoxyphenylthio)benzoate

Dissolve 115 g of the acid of Step A in 3.5 liters of methanol and addslowly 25 ml of sulfuric acid. Stir under reflux for 72 hours. Cool thereaction mixture to room temperature and add 100 g of sodium bicarbonatein portions. Stir for an additional hour and strip to dryness. Dissolvethe residue in methylene chloride and wash the solution three times withwater. Dry the solution and strip to an oil which solidifies. (m.p.82°-84° C.)

Step C 3-(o-Carbomethoxypheylthio-)4-methoxybenzaldehyde

Dissolve 117 g (0.427 mole) of the ester of Step B in 1500 ml of1,2-dichloroethane and cool with stirring in an ice-bath. Add 200 ml(345 g, 1.82 mole) of titanium tetrachloride at a rapid dropwise rate.Add also fairly rapidly 154 g (1.34 mole) of dichloromethyl methylether. Stir the mixture under a nitrogen atmosphere overnight then pourinto ice. After shaking, separate the organic phase and extract theaqueous phase twice with methylene chloride. Wash the combined organicphases twice with water, dry and strip to an oil which crystallizes.(m.p. 99°-104° C.).

Step D 3-(o-Carboxyphenylthio)-4-hydroxybenzaldehyde

Heat 126 g of the aldehyde of Step C in a mixture of 1500 ml of glacialacetic acid and 1500 ml of 48% hydrogen bromide in an oil bath at 150°C. with mechanical stirring until no trace of nondemethylated productremains (4-5 days). Col the reaction mixture and pour into 7 liters ofwater. Separate the precipitate, wash well with water and dry in vacuoat 70° C. to constant weight. (Yield: 108.2 g).

Step E 3-(o-Carboxyphenylthio)-4-hydroxybenzonitrile

Reflux 91.3 g of the aldehyde of Step D, 27.4 g of hydroxylaminehydrochloride and 41.9 g of sodium formate in 900 ml of formic acid(98-100%) for 11/4 hours. Cool the mixture and pour into 21/2 liters ofcold water. Separate the precipitate, wash with water and dry in vacuoat 75° C. (Yield: 82 g).

Step F 2-Cyano-6H-6-oxo-dibenzo[b,e][1,4]oxathiepin

Stir together at room temperature overnight 8.4 g of the nitrile of StepE and 19.16 g (3 molar equivalents) of dicyclohexylcarbodiimide in 400ml of ethyl acetate. Filter the reaction mixture to remove the urea.Strip the filtrate to dryness. Triturate the residue in a small volumeof ethyl acetate and filter. (Yield 5.5 g purple solid).

Strip the filtrate to dryness and chromatograph on a column of silicagel, eluting with benzene. (Yield 2.1 g white solid), (yield total: 7.6g).

Step G 3-(o-Hydroxymethylphenylthio-)4-hydroxybenzonitrile

Dissolve 31.25 g (0.123 mole) of the nitrile of Step F in 750 ml oftetrahydrofuran and add 10.4 g (0.274 moles) of sodium borohydride. Stirthe solution at room temperature for 11/2 hours. Add water in smallportions until foaming ceases. Remove the tetrahydrofuran byevaporation. Shake the residue with ethyl acetate, water and dilutehydrochloric acid. Separate the organic phase and extract the aqueousphase three times with ethyl acetate. Wash the combined organic phaseswith two small volumes of water, dry and strip to a thick oil whichsolidifies. (Yield: 39 g).

Step H 2-Cyano-6H-dibenz[b,e][1,4]oxathiepin

Stir the crude nitrile of Step F (assumed 100% yield, 0.123 mole) and 38g (50% excess) of dicyclohexylcarbodiimide at 105°-110° C. for 11/2hours. Cool the reaction mixture and extract with methylene chloride.Filter to remove the dicyclohexylurea and strip the filtrate to dryness.Triturate in a small volume of ethyl acetate, filter and strip todryness. Extract four times with hot benzene and strip the combinedextracts to dryness. Chromatograph on a silica gel column, eluting withbenzene to obtain the title product. (m.p. 145°-147° C.).

EXAMPLE 10 6H-Dibenzo[b,e][1,4]oxathiepin-2-carboxylic acid

Reflux 3.2 g of the nitrile of Example 9 for 5 hours in a mixture of 50ml of 20% sodium hydroxide and 50 ml of ethanol. Allow the resultingclear solution to stand at room temperature overnight. Evaporate theethanol. Dilute the residue with 200 ml of water and heat on a steambath to dissolve. Filter and acidify the filtrate. Separate theprecipitate, wash and dry in vacuo at 75° C. to obtain the titleproduct. (m.p. 225°-227° C.).

EXAMPLE 11 6H-Dibenz[b,e][1,4]oxathiepin-2-carboxylic acid 11-oxide

Suspend 2 g of the acid of Example 10 in 70 ml of acetic acid and add 7ml of 30% hydrogen peroxide. Heat at 55° C. for 21/2 hours. Cool thereaction mixture to room temperature. Separate the precipitate, washwith acetic acid and dry. Dissolve the product in 150 ml of boilingtetrahydrofuran and filter. Concentrate the filtrate to 50 ml. Cool andseparate the precipitate to obtain the title product. (m.p. 284°-286° C.slow dec.).

EXAMPLE 12 6H-Dibenz[b,e][1,4]oxathiepin-2-carboxylic acid-11,11-dioxide

Suspend 1.3 g of the acid of Example 10 in 50 ml of glacial acetic acicand add 7 ml of 30% hydrogen peroxide. Heat slowly to 75° C. and stirfor 5 hours. Allow the reaction mixture to stand at room temperatureovernight. Separate the precipitate, wash with acetic acid and dry toobtain the title product. (m.p. 279°-282° C.).

EXAMPLE 13 2-(1H-Tetrazol-5-yl)-6H-dibenz[b,e][1,4]oxathiepin

Reflux 3 g (12.55 mmole) of the nitrile of Example 9, 1 g (15.4 mmole)of sodium azide and 1 g (18.7 mmole) of ammonium chloride in 40 ml ofdimethylformamide overnight. Cool to room temperature. Add aqueoussodium bicarbonate and ethyl acetate and stir the mixture for 30minutes. Separate the aqueous phase and extract with ethyl acetate.Acidify the aqueous phase and separate the title product by filtration.(m.p. 230° C. dec.).

EXAMPLE 14 2-(1H-Tetrazol-5-yl)-6H-dibenz[b,e][1,4]oxathiepin-11-oxide

Suspend 2 g of the tetrazolyl compound of Example 13 in 120 ml of aceticacid. Add 15 ml of 30% hydrogen peroxide. Place the reaction mixture inan oil bath and heat slowly to 60° C. Stir at 60° C. for 2 hours. Coolto room temperature, filter, wash the precipitate with acetic acid anddry to obtain the title product. (m.p. 282° C. dec.).

EXAMPLE 152-(1H-Tetrazol-5-yl)-6H-dibenz[b,e][1,4]oxathiepin-11,11-dioxide

Suspend 600 mg of the tetrazole compound of Example 13 in 40 ml ofglacial acetic acid and add 5 ml of 30% hydrogen peroxide. Heat to70°-75° C. for 21/2 hours until a clear solution is obtained. Cool thereaction mixture to room temperature. Separate the precipitated titleproduct, wash with acetic acid and air dry. (m.p. 255° C. dec.).

EXAMPLE 16 Methyl 6H-dibenz[b,e][1,4]oxathiepin-9-carboxylate Step A9-Chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin

Dissolve 5.16 g of 6H-dibenz[b,e][1,4]oxathiepin-9-carboxylic acid in100 ml of chloroform and 50 ml of thionyl chloride and add to themixture 1.0 ml of dimethylformamide. Allow the mixture to stand at roomtemperature for 72 hours. Evaporate the mixture to dryness to obtain thedesired acid chloride.

Step B Methyl 6H-dibenz[b,e][1,4]oxathiepin-9-carboxylate

Dissolve 2.0 g of the acid chloride of Step A in 20 ml oftetrahydrofuran containing 1.0 ml of methanol and 4 ml of pyridine.Allow the mixture to stand at room temperature for 24 hours thenevaporate to dryness. Dissolve the residue in 1:4 ether/hexane andfilter through silica gel. Evaporate the filtrate to dryness to obtainthe title product.

Employing the process of Example 16, but substituting another loweralkanol such as, for example, ethanol, 2-propanol, butanol or 2-butanol,for the methanol of Step B, the corresponding lower alkyl esters of6H-dibenz[b,e][1,4]-oxathiepin-9-carboxylic acid are obtained.

EXAMPLE 17 Methyl 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate

Repeat the process of Example 16, substituting6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid for the6H-dibenz[b,e][1,4]oxathiepin-9-carboxylic acid of Step A, in order toobtain the title product. By substituting, where desired, other loweralkanols such as, for example, ethanol, 2-propanol, butanol or2-butanol, for the methanol of Step B, the corresponding lower alkylesters of 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid are obtained.

EXAMPLE 18 6H-Dibenzo[b,e]1,4]oxathiepin-2-carboxamide Step A2-Chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin

Heat a solution of 5 g of 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylicacid and 40 ml of thionyl chloride under reflux for 20 minutes.Evaporate the reaction mixture under vacuum to dryness. Repeat theevaporation with two 30 ml portions of carbon tetrachloride. Crystallizethe residue from diisopropyl ether to obtain the title product.

Step B 6H-Dibenzo[b,e][1,4]oxathiepin-2-carboxamide

Dissolve the acid chloride from Step A in 20 ml of dry tetrahydrofuranand add this solution dropwise with stirring to a cooled (ice-bath)saturated solution of ammonia in 60 ml of tetrahydrofuran. Pass ammoniathrough the reaction mixture continuously for 15 minutes. Stir at roomtemperature for an additional 15 minutes and evaporate the reactionmixture to dryness. Add a mixture of 12 ml of ethanol and 60 ml of waterto the residue and stir at room temperature for an additional 30minutes. Separate the solid by filtration and wash with water, then withethanol and then with ether. Dry in vacuo to obtain the title product.

In a similar manner, substituting6H-dibenz[b,e][1,4]oxathiepin-9-carboxylic acid for the6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid in Step A, there isobtained 6H-dibenz[b,e][1,4]oxathiepin-9-carboxamide.

EXAMPLE 19 6H-Dibenzo[b,e][1,4]oxathiepin-2-N-methylcarboxamide

Add 6.0 g of 2-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin to 4 g ofmethylamine in 100 ml of methylene chloride at 0°-5° C. Add 13 ml oftriethylamine dropwise over 10 minutes then stir the reaction mixture atroom temperature overnight. Extract the reaction mixture with water, drythe organic layer and evaporate to dryness. Chromatograph over silicagel eluting with 200:20 toluene/dioxane. Evaporate eluate to dryness andrecrystallize residue from methanol to obtain the title product.

In a similar manner, substituting another N-loweralkylamine such as, forexample, ethylamine, propylamine, isopropylamine, butylamine and thelike, or a N,N-di-loweralkylamine such as, for example, dimethylamine,diethylamine, dipropylamine, dibutylamine and the like, for themethylamine employed above, there is obtained the corresponding6H-dibenz [b,e][1,4]oxathiepin-2-N-loweralkylcarboxamide or2-N,N-di-loweralkylcarboxamide. Corresponding6H-dibenz[b,e][1,4]oxathiepin-9-N-loweralkylcarboxamides and9-N,N-di-loweralkylcarboxamides are prepared by substituting9-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin for the2-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin employed above.

Also in a similar manner, substituting a carboxyloweralkylamine such as,for example, glycine, valine, leucine, isoleucine and the like, or theN-loweralkyl derivatives thereof, such as for example, N-methylglycine,N-propyleucine, N-butylisoleucine and the like, there is obtained thecorresponding 6H-dibenz[b,e][1,4]oxathiepin-9-(or2-)carboxyloweralkylcarboxamides or the N-loweralkyl derivativesthereof.

EXAMPLE 20 6H-Dibenz[b,e][1,4]oxathiepin-2-N-methanesulfonylcarboxamide

Heat 5.0 g of 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid in 50 mlof thionyl chloride for 15 minutes at reflux and then distill off theexcess thionyl chloride. Evaporate the residue twice with small volumesof benzene. Add the resulting acid chloride to 4.0 g ofmethanesulphonamide in 100 ml of methylene chloride at 0°-5° C. Adddropwise over 10 minutes 15 ml of triethylamine. Stir the mixture atroom temperature overnight. Extract the reaction mixture with 100 ml of0.5N sodium hydroxide, wash the alkaline extract with ether and acidifywith 6N hydrochloric acid. Separate the solids by filtration and dry invacuo over potassium hydroxide. Chromatograph over silica gel elutingwith 200:20:3 toluene/dioxane/acetic acid. Evaporate the eluate todryness and recrystallize the residue from methanol to obtain the titleproduct.

In a similar manner, substituting another loweralkylsulphonamide suchas, for example, ethanesulphonamide, propanesulphonamide,butanesulphonamide and the like, for the methanesulphonamide employedabove, there is obtained the corresponding6H-dibenz[b,e][1,4]oxathiepin-2-N-loweralkylsulfonylcarboxamide.Corresponding6H-dibenz[b,e][1,4]oxathiepin-9-N-loweralkylsulfonylcarboxamides areprepared by substituting 6H-dibenz[b,e][1,4]-oxathiepin-9-carboxylicacid for the 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid employedabove.

EXAMPLE 216H-Dibenz[b,e][1,4]oxathiepin-2-(3-methyl-2-thiazolidinylidene)carboxamide

Reflux 1.0 g of 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid in 15 mlof thionyl chloride for 30 minutes. Strip the reaction mixture todryness and dissolve the residue in 25 ml of methylene chloride. Add asolution of 1.0 g of 2-imino-3-methylthiazolidine in 10 ml of methylenechloride. Stir at room temperature for 30 minutes and add water.Continue stirring for 10 minutes. Separate the organic phase and washwith water and dry overnight over sodium sulfate. Strip to dryness. Stirand triturate the residue in ether, then in methanol. Chromatograph theresulting solid over silica gel, eluting with 20% ethylacetate inbenzene. Strip to dryness to obtain the title product.

EXAMPLE 222-(3-Hydroxy-1,2,5-thiadiazol-4-yl)-6H-dibenz[b,e][1,4]oxathiepin Step A6H-Dibenz[b,e][1,4]oxathiepin-2-carboxaldehyde

Heat a mixture of 5.0 g of 2-cyano-6H-dibenz[b,e][1,4]oxathiepin and 4.0g of Raney nickel alloy in 60 ml of 75% (v/v) aqueous formic acid atreflux for 1.5 hours. Cool to room temperature and filter. Concentrateto small volume and extract with methylene chloride. Wash the extractwith water and with 1N sodium bicarbonate until neutral. Dry the neutralextract over sodium sulfate and concentrate to dryness to obtain thetitle product.

Step B 6H-Dibenz[b,e][1,4]oxathiepin-2-(2-aminoacetonitrile)

Stir at room temperature for 12 hours a mixture of 5.85 g of ammoniumchloride, 5.3 g of sodium cyanide 75 ml of ammonium hydroxide, 100 ml ofethanol saturated with ammonia and 12 g of the carboxaldehyde of Step A.Pour the reaction mixture into 300 ml of water and extract with ether.Dry the extract over sodium sulfate and concentrate to dryness to obtainthe title product.

Step C 6H-Dibenz[b,e][1,4]oxathiepin-2-(2-aminoacetamide)

Stir at room temperature 5.0 g of the aminoacetonitrile of Step B in 30ml of concentrated hydrochloric acid for 30 minutes. Slowly pour thereaction mixture into cold ammonium hydroxide. Extract the mixture withether and dry over sodium sulfate. Evaporate the extract to dryness toobtain the title product.

Step D 2-(3-Hydroxy-1,2,5-thiadiazol-4-yl)-6H-dibenz[b,e][1,4]oxathiepin

Stir overnight at room temperature a mixture of 1.365 g of theaminoacetamide of Step C, 1.989 g of sulfur monochloride and 5 ml ofdimethylformamide. Filter the reaction mixture and then partitionbetween ice-water (75 ml) and ethyl acetate (75 ml). Filter, separatethe organic layer, wash with saturated aqueous sodium chloride solutionand dry over magnesrum sulfate. Evaporate to dryness and dissolve theresidue in 200 ml of boiling ethanol, treat with charcoal and filter.Concentrate to 25 ml, and separate the solids by filtration to obtainthe title proouct.

By substituting 9-cyano-6H-dibenz[b,e][1,4]oxathiepin for the2-cyano-6H-dibenz[b,e][1,4]oxathiepin employed in Step A above, there isobtained the corresponding9-(3-hydroxy-1,2,5-thiadiazol-4-yl)-6H-dibenz[b,e][1,4]oxathiepin.

EXAMPLE 23 2-(4-Hydroxy-Δ³-pyrrolin-3-yl-2,5-dione)-6H-dibenz[b,e][1,4]oxathiepin Step A2-Hydroxymethyl-6H-dibenz[b,e][1,4]oxathiepin

Dissolve 5.1 g of 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid in 100ml of tetrahydrofuran and add 35 ml of 1M borane in tetrahydrofuran atroom temperature under a nitrogen atmosphere. Stir the mixture at roomtemperature for 3 hours. Slowly dilute the reaction mixture with waterand then with ethyl acetate. Wash with aqueous sodium chloride, dry andevaporate to an oil. Yield 4.93 g (crude).

Step B 2-Bromomethyl-6H-dibenz[b,e][1,4]oxathiepin

Dissolve 4.43 g of the crude alcohol of Step A in 100 ml of benzene andadd 1 ml (10.5 mmole) of phosphorous tribromide. Stir at roomtemperature for 1 hour, add water and then dilute with toluene. Washthree times with water, dry and strip to a solid residue. (Yield, 6.9 g,holding toluene)

Step C 2-Cyanomethyl-6H-dibenz[b,e][1,4]oxathiepin

Dissolve 6.4 g of the bromide of step in 75 ml of dimethylformamide andadd 2.95 g of sodium cyanide. Stir the mixture at room temperature for1.5 hours. Dilute with 600 ml of water and extract three times withether. Wash the combined organics with water, dry and strip to a solidresidue. Triturate in hexane and recover the solid by filtration. (m.p.105°-107° C.)

Step D 6H-Dibenzo[b,e][1,4]oxathiepin-2-acetic acid

Reflux 2.0 g of the nitrile of Step C in a mixture of 30 ml of 20%aqueous sodium hydroxide and 30 ml of ethanol for four hours. Strip awaythe alcohol, wash with ethyl acetate and acidify the aqueous phase withhydrochloric acid. Separate the precipitate by filtration. Wash withwater and dry. (m.p. 144°-146° C.)

Step E 6H-Dibenzo[b,e][1,4]oxathiepin-2-acetamide

Reflux for 20 minutes a mixture of 5.0 g of the acid of Step D and 40 mlof thionyl chloride. Evaporate to dryness under vacuum. Evaporate twicewith 30 ml portions of carbon tetrachloride. Dissolve the residue in 20ml of tetrahydrofuran and add the solution dropwise to a cooled andstirred saturated solution (ice-bath) of ammonia in 60 ml oftetrahydrofuran. Pass ammonia through the solution simultaneously.Continue stirring at room temperature for an additional 15 minutes.Evaporate the mixture to dryness. Add a mixture of 12 ml of ethanol and60 ml of water and stir the suspension for 30 minutes. Separate thesolids and wash with water, then with ethanol and finally with ether toobtain the title product.

Step F 2-(4-Hydroxy-Δ³-pyrrolin-3-yl-2,5-dione)-6H-dibenz[b,e][1,4]oxathiepin

Stir at room temperature a mixture of 5.118 g of the amide of Step E,2.939 g of diethyl oxalate, 4.723 g of potassium t-butoxide and 40 ml ofdimethylformamide for 6 hours. Pour the reaction mixture into 300 ml ofice-water and extract with 300 ml of ethyl acetate. Acidify with 6Nhydrochloric acid and separate the ethyl acetate layer. Wash withsaturated sodium chloride solution and dry. Evaporate to dryness anddissolve the residue in warm dioxane. Treat with a slight excess ofammonia and separate the solid by filtration. Wash with dioxane and dry.Suspend the product in water, acidify with 6N hydrochloric acid andextract with ethyl acetate. Wash the extract with saturated sodiumchloride solution, dry over magnesium sulfate and evaporate to obtainthe title product.

EXAMPLE 24 β-Hydroxyethyl 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate

To a stirred solution of 1.0 g of2-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin in 50 ml of methylenechloride, add 3 g of ethylene glycol and stir the mixture for 18 hoursat room temperature. Distill off the solvent and excess ethylene glycolunder high vacuum (0.1 mm). Chromatograph the residue on a silica gelcolumn (100 g), eluting with 10% ethyl acetate in benzene to obtain thetitle product.

In a similar manner, substituting another loweralkyldiol such as, forexample, trimethylene glycol and 1,4-butanediol and the like for theethylene glycol, there is obtained the correspondinghydroxyloweralkylester. The corresponding hydroxyloweralkyl9-carboxylate esters are prepared by substituting 9-chlorocarbonyl6H-dibenz[b,e][1,4]oxathiepin for the 2-chlorocarbonyl6H-dibenz[b,e][1,4]oxathiepin employed above.

EXAMPLE 25 β-Dimethylaminoethyl6H-dibenz[b,e][1,4]oxathiepin-9-carboxylate

Dissolve 1.0 g of 9-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin asprepared in Example 16, Step A, in 10 ml of anhydrous tetrahydrofuranwith stirring and add 2 ml of N,N-dimethylethanolamine. Stir at roomtemperature for 18 hours and strip the mixture to dryness. Partition theresidue between ether and dilute hydrochloric acid and separate theaqueous layer. Basify the aqueous layer with aqueous ammonia and extractwith ethyl acetate. Evaporate the organic phase and chromatograph theresidue over silica-gel eluting with 90% chloroform in methanol toobtain the title product.

In a similar manner, substituting anotherN,N-diloweralkylaminoloweralkanol such as, for example,diethylethanolamine, 3-N,N-dimethylaminopropan-1-ol,4-N,N-diethylaminobutan-1-ol and the like, for theN,N-dimethylethanolamine there is obtained the correspondingN,N-diloweralkylaminoloweralkyl ester. The correspondingN,N-diloweralkyl 2-carboxylate esters are prepared by substituting2-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin for the9-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin employed above.

EXAMPLE 266H-Dibenz[b,e][1,4]oxathiepin-2-N-carboxyloweralkylcarboxamide

Reflux 1.0 g of 2-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin in 20 mlof ethyl acetate containing 2.0 g of glycine for 5 hours. Evaporate themixture to dryness. Add 30 ml of water to the solid residue and stir atroom temperature for one hour. Separate the solid by filtration andrecrystallize from ethanol to obtain the title product.

In a similar manner, substituting another amino acid such as, forexample, alanine or valine and the like for the glycine, there isobtained the corresponding 2-carboxyloweralkylcarboxamide.

The corresponding 9-carboxyloweralkylcarboxamides are prepared bysubstituting 9-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin for the2-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin employed above.

EXAMPLE 27 β-Carboxyethyl 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate

Dissolve 1.0 g of 2-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin in 20ml of tetrahydrofuran and add 1.0 g of the sodium salt ofβ-hydroxypropionic acid. Stir the mixture at room temperature for 18hours. Filter and evaporate the filtrate to dryness. Recrystallize thesolid residue from ethanol to obtain the title product.

In a similar manner, substituting another hydroxyloweralkanoic acid saltsuch as, for example, an alkali metal salt of hydroxyacetic acid,3-hydroxybutyric acid and the like, for the β-hydroxypropionic acidsodium salt, there is obtained the correspondingcarboxyloweralkyl-2-carboxylate ester. The correspondingcarboxyloweralkyl-9-carboxylate esters are prepared by substituting9-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin for the2-chlorocarbonyl-6H-dibenz[b,e][1,4]oxathiepin employed above.

EXAMPLE 28 2-(1H-Tetrazol-5-yl-methyl)-6H-dibenz[b,e][1,4]oxathiepin

Add to 25 ml of tetrahydrofuran cooled in an ice-bath 1.59 g (11.9mmole) of aluminum chloride, 1.33 g (5.25 mmole) of2-cyanomethyl-6H-dibenz[b,e][1,4]oxathiepin and 1.55 g (23.8 mmole) ofsodium azide. Reflux the mixture for 19 hours, cool, dilute with waterand acidify. Extract the mixture into ethyl acetate and evaporate.Triturate the residue in ether and separate the title product byfiltration. (m.p. 193°-195° C.).

EXAMPLE 29

6H-Dibenz[b,e][1,4]oxathiepin-2-acetic acid-11,11-dioxide

Heat 600 mg of 6H-dibenz[b,e][1,4]oxathiepin-2-acetic acid to 80°-85° C.in a mixture of 30 ml of glacial acetic acid and 5 ml of 30% hydrogenperoxide for 3 hours. Dilute with water to final volume of about 250 ml.Separate the title product by filtration. (m.p. 188°-190° C.).

EXAMPLE 30N-(Carboxymethyl)-6H-dibenz[b,e][1,4]oxathiepin-2-carboxamide-11,11-dioxideStep AN-(Carbomethoxymethyl)-6H-dibenz[b,e][1,4]oxathiepin-2-carboxamide11,11-dioxide

Suspend 1.161 g of the acid of Example 12 in 70 ml THF and add 2.52 mlof triethylamine followed by 0.43 ml of ethylchloroformate. Stir themixture at room temperature for 5 minutes. Add in portions 1.134 gglycine methyl ester HCl. Stir at room temperature for twenty-fivehours. Filter and wash the collected solids with THF. Evaporate thecombined THF and filtrate to dryness. Dissolve the residue in methylenechloride, add 10 g silica gel and evaporate the methylene chloride.Place the residue atop a silica gel column and elute with 50:50 ethylacetate/toluene. Remove the solvent to obtain the title product. (m.p.169°-172° C.).

Step BN-(Carboxymethyl)-6H-dibenz[b,e][1,4]oxathiepin-2-carboxamide-11,11-dioxide

Suspend 542 mg of the methyl ester from Step A and 84 mg of lithiumhydroxide hydrate in a mixture of 10 ml water and 10 ml THF. Stir atroom temperature for 1.5 hours. Dilute the mixture with 20 ml of wateracidified with 2N HCl and extract the mixture with ethyl acetate. Washthe ethyl acetate extracts with saturated sodium chloride solution anddry. Evaporate the solution to dryness. Triturate the resulting solidwith ether to obtain the title product. (m.p. 235° C.).

EXAMPLE 31 9-Fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid StepA Bis-(2-carboxy-5-nitrophenyl)disulfide)

2-Amino-4-nitrobenzoic acid (18 g, 0.1 mole) was added to water (90 ml)and the mechanically stirred slurry was placed in an ice and water bath;there was then added slowly sulfuric acid (30 ml over about 10 min) sothat the temperature did not go over 25°; solution did not occur, butthe mixture became less viscous; this suspension was cooled down to 5°and stirred at that temperature for 20 minutes. Then there was begun theslow addition of a solution of sodium nitrite (11.7 g, 98%, 0.166 mole)in water (18 ml). The addition was done in small portions over 1 hour,each portion added beneath the surface of the mixture. Toward the end ofthe addition, frothing occurred. After the addition of the mixture wasstirred for a further 11/2 hour at 0°. The mixture was filtered and thefiltrate kept cold. The cold filtrate was added dropwise to a solutionof sodium carbonate (100 g) and ethyl xanthic acid potassium salt (18 g)in water (750 ml) preheated to 50° in an oil bath. The displacement ofthe diazonium salt was immediate as each drop caused gassing. Theresulting red solution was heated up to 70° (internal) and stirred atthat temperature for 3 hours. There was then added more Na₂ CO₃ (25 g)and the heating and stirring was continued for 21/2 hours. The mixturewas allowed to cool to room temperature and stirred overnight.

A small amount of solid had separated and it was filtered off. Thefiltrate was acidified slowly with conc. HCl affording a sticky solidwhich was filtered. The crude product was heated in 40 ml acetic acid ona steam bath for 1/2 hour, then the mixture was allowed to cool and stirat room temperature overnight.

The insolubles were filtered to yield an orange solid, 11.76 g.

The crude product was dissolved in 500 ml boiling acetone. The mixturefiltered hot, concentrated until crystallization began; allowed to cooldown and stand for a few hours, then filtered to yield the titlecompound, 44 g, as an orange solid.

Step B 2-Mercapto-4-nitrobenzyl alcohol

The compound of Step A above (9.50 g, 24 mmoles) was dissolved in THF(100 ml) and the mixture placed under N₂ atmosphere. There was addedslowly a 1.1M BH₃ /THF solution (50 ml) an the mixture stirred at roomtemperature overnight. The mixture had become a slurry containing agelatinous solid. There was next added additional BH₃ solution (25 ml)and after 3 hours the solids had dissolved partly and TLC showed amixture of I and II (the title compound). Additional borane solution (25ml) was added and the mixture stirred overnight at room temperature. Aclear amber solution had formed and TLC showed only product and a newless polar spot. There was added carefully, water (50 ml) and the THFwas evaporated away leaving a yellow solid and the aqueous fraction.This was partitioned between EtOAc and in Na₂ CO₃. The organic layercontained the unknown side-product (I) and the aqueous phase containedthe title compound. Acidification of the aqeuous phase and extractionwith EtOAc afforded the title compound as a yellow solid, 3.07 g.

Step C 3-(2-Hydroxymethyl-5-nitrophenylthio)-4-hydroxybenzoic acid

A mixture of 2-mercapto-4-nitrobenzyl alcohol 9.49 g, 18.86 mmoles),4-hydroxy-3-iodo-benzoic acid (4.67 g, 17.69 mmoles), red cuprous oxide(1.35 g, 9.44 mmoles) and 1-methyl-2-pyrrolidinone (40 ml) was heatedunder a N₂ atmosphere. The mixture became a thick slurry at 90° but at130° had become a dark red solution. After 1/2 hour at 140° TLC showedthat the reaction was finished. The mixture was poured onto 2N HCl (200ml) and after stirring for a few minutes it was extracted 4× with EtOAc.The EtOAc extracts were washed with water, then extracted 4× with 1NNaOH. The aqueous extracts were washed once with EtOAc then acidifiedand the resulting solid filtered, washed with water and dried to yield4.65 g of the title compound.

Step D Methyl 3-(2-hydroxymethyl-5-nitrophenylthio)-4-hydroxy benzoate

The crude acid from Step C above (4.65 g) was refluxed with methanol(250 ml) containing H₂ SO₄ (5 ml). After 5 hours TLC showed no more acidpresent. The methanol was evaporated away almost completely and therewas added water (25 ml) and, carefully, there was added solid NaHCO₃until all of the acid had been neutralized. The ester was extracted intoEtOAc (3×) and the combined organics washed with water (3×), dried overNa₂ SO₄ and evaporated to yield the title compound as a brown solid(4.54 g).

Step E Methyl 9-nitro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate

The ester from Step D above (4.54 g, 13.55 mmoles) was dissolved in THF(100 ml) and there was added diethyl azodicarboxylate (3.0 g, 16.4mmoles); the solution was cooled in an ice and water bath, and there wasadded slowly a solution of triphenylphosphine (4.25 g, 16.22 mmoles) inTHF (30 ml). After the addition, the mixture was stirred in the cold for15 minutes and the cooling bath was removed. When the temperature hadrisen to room temperature, TLC showed that the reaction was over, butstirring was continued overnight. The mixture was evaporated to drynessand the residue dissolved in boiling EtOAc (100 ml). The mixture wasconcentrated to 70 ml by boiling away the solvent. Then the mixture wasallowed to cool down to room temperature. After 4 hours the crystallinematerial was filtered and dried affording the title compound as a yellowfluffy solid. m.p.: 178°-179°. The filtrate was stripped down and theresidue dissolved in CH₂ Cl₂ and chromatographed on a column of silicagel, eluting with CH₂ Cl₂ ; there was obtained 1.2 g of the titlecompound contaminated with a small amount of more polar material. Thiswas crystallized from EtOAc and there was obtained 0.73 g of the titlecompound.

Step F Methyl 9-amino-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate

The ester from Step E above (2.83 g, 8.93 mmole) was suspended in THF(40 ml) and conc. HCl (8 ml) was added. Next was added stannous chloridedihydrate (6.63 g, 23 mmoles). The mixture was stirred at roomtemperature overnight. The reaction was not complete so additionalSnCl₂.2H₂ O (2 g) was added and stirring was continued for 7 hours,whereupon TLC showed completeness of the reduction. The mixture wasdiluted with 1N NaOH (100 ml) and EtOAc. The presence of tin salts madeextraction difficult so they were filtered through a bed of Celite. Theorganic extracts (3×) were washed with saturated NaCl solution twice,then dried over Na₂ SO₄ overnight. The solution was then evaporated toan oil (8 g). Addition of water caused separation of an orange solidwhich was filtered, washed with water and dried to yield thehydrochloride salt of the title compound, m.p.: >200°. The original tinsalt and Celite residues were found to contain product; not enough basehad been used. They were suspended in 1N NaOH (100 ml) extracted againwith EtOAc. The extracts washed with water, dried over Na₂ SO₄ strippeddown to an orange solid which was titrated with water and filtered. Thesolid was dried affording 1.55 g of the title compound, m.p. 155°-157°.

Step G Methyl 9-fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate

The amine ester from Step F above (1.45 g, 5.05 mmoles) was suspended inconc. HCl (21 ml) and the mixture stirred vigorously for 10 minutes atroom temperature, then cooled in an ice, salt and water bath. At 5° C.there was begun the addition of a cold solution of sodium nitrite (710mg, 10.3 mmole) in water (5 ml). This addition was done over 10 minutes,the solution being added in portions below the surface of the reactionmixture. After the addition, the frothing mixture was stirred in thecold for a further 10 minutes then there was added 48% fluoroboric acid(21 ml) pre-cooled. This caused separation of a yellow solid. Thesuspension was stirred in the cold for 15 minutes then the solid wasfiltered, washed with cold 24% HBF₄ solution and air dried overnight.the slightly damp solid was added portionwise to decalin (15 ml)preheated to 100°. Each addition of a portion caused frothing; after theaddition the mixture was stirred at 100° for a further 20 minutes, thenthe liquid portion was decanted and the insolubles extracted twice withboiling toluene (10 ml). The combined extracts and original decalinsolution was cooled and injected as such to a column of silica gel (100g) packed in toluene. Elution with toluene afforded the title compoundas a white solid, 310 mg, m.p.: 131°-132° C.

Step H 9-Fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid

The ester from Step G above (395 mg) was heated at 50°-55° C. in amixture of 20% aqueous NaOH (10 ml) and DAG-ethanol (10 ml) for 2 hours.The mixture was concentrated to 1/2 volume, diluted with water (20 ml).The solids (Na salt of acid) did not dissolve even on warming. The warmmixture was stirred and acidified with 20% aqueous HCl. The resultingsuspension was stirred for 20 minutes at room temperature to afford thetitle compound as a white solid.

EXAMPLE 32 9-Fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylicacid-11,11-dioxide

Following the procedure of Example 29 but substituting an equivalentamount of the acid of Example 31, Step H, for the acid of Example 23,Step D, there is obtained the title compound.

EXAMPLE 33 8-Fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid

Following the procedure of Example 31, Steps A-F, but substituting anequivalent amount of 2-amino-5-nitrobenzoic acid for2-amino-4-nitrobenzoic acid in Step A there were obtained the followingcompounds:

Step A: 15.72 g of bis-(2-carboxy-4-nitrophenyl)disulfide

Step B: 3.1 g of 2-mercapto-5-nitrobenzyl alcohol

Step C: 4.07 g of 3-(2-hydroxymethyl-4-nitrophenylthio)-4-hydroxybenzoic acid

Step D: 2.64 g of methyl 3-(2-hydroxymethyl-4-nitrophenylthio)-4-hydroxybenzoate, m.p. 180°-183° C.

Step E: 6.15 g of methyl8-nitro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate, m.p. 225°-226° C.

Step F: 144 mg of methyl8-amino-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate, m.p. 154°-155° C.

Step G: Methyl 8-diazonium-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylatefluoroborate salt

The amino ester from Step F above (780 mg, 2.72 mmoles) was suspended inconc. HCl (10 ml) and the mixture was stirred vigorously at roomtemperature for 10 minutes. The solid had become a fine suspension. Themixture was cooled in an ice and salt bath and at 0° there was addedslowly (over 10 minutes) a cold solution of sodium nitrite (540 mg, 7.83mmoles) in water (1.5 ml). The mixture turned red-orange and the solidsdissolved almost completely, then a new orange solid separated out. Themixture was stirred at 0° C. for 15 minutes then there was addeddropwise (10 ml) pre-cooled 48% fluoroboric acid (10 ml). The orangesolid became yellow and the resulting suspension was stirred in the coldfor 1 hour, then filtered, washed with cold 25% HBF₄ solution and airdried overnight affording the title compound (1.46 g) as a yellow solid.

Step H Methyl 8-fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate

The crude diazonium salt from Step G above (1.31 g) was placed in a 50ml flask, immersed in an oil bath preheated to 105° and a slight vacuumwas applied. Within a few moments the solid began to melt and evolvegas. Heating was continued for 20 minutes, then the mixture was cooledand dissolved in THF (all soluble); there was added 5 grams of silicagel, the mixture evaporated to dryness and the solids placed atop acolumn of 50 g silica gel. Elution with toluene afforded the titlecompound (170 mg) as a yellow solid, m.p.: 119°-121° C.

Step I 8-Fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylic acid

The ester from Step H above (200 mg) was stirred at room temperature ina mixture of 20% aqueous NaOH (10 ml) and THF (10 ml) overnight. Verylittle hydrolysis had occurred. The mixture was brought to reflux. After6 hours refluxing was stopped; TLC showed mostly product and a residualless polar spot (weak) which seemed to be very slightly different fromthe starting ester. The biphasic mixture containing solids was allowedto stir at room temperature overnight. The mixture was diluted withwater and EtOAc. The aqueous fraction was collected, leaving behind theorganic layer and solids. The organic phase was extracted with water andthe solids dissolved. The aqueous phases were combined. Some solids cameout of solution. The aqueous suspension was warmed on a steam bath to50° and acidified with 12N HCl. A fluffy white solid came out. Thesuspension was cooled down to room temperature and filtered. The solidwas washed with water and dried affording the title compound (90 mg),m.p.: 278°-280° C.

EXAMPLE 34 8-Fluoro-6H-dibenz[b,e][1,4]oxathiepin-2-carboxylicacid-11,11-dioxide

Following the procedure of Example 29, but substituting an equivalentamount of the acid of Example 33, Step I, for the acid of Example 23,Step D, there is obtained the title compound.

EXAMPLE 352-[1-(Pivalyloxy)ethoxycarbonyl]-6H-dibenz[b,e][1,4]oxathiepin-11,11-dioxide

To a mixture of 204 mg 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylicacid-11,11-dioxide (0.7 mmole) and 1.5 gram of anhydrous potassiumcarbonate in 10 ml of dimethyl formamide, there was added a solution of390 mg 1-chloroethyl pivalate (2.3 mmole) in 10 ml of dimethylformamide. The reaction mixture was stirred at ambient temperature for24 hours, then it was partitioned between water and ethyl acetate. Thecrude product obtained from evaporation of the organic phase waschromatographed on a column of silica gel, eluting with dichloromethane,to isolate the ester which was stirred in a small amount of ether for 4hours then filtered. The yield was 141 mg, m.p.: 136°-137°.

EXAMPLE 36 Methyl 6H-dibenz[b,e][1,4]oxathiepin-2-carboxylate11,11-dioxide

To a suspension of 350 mg of the acid of Example 12 in 10 ml of methanoladd a solution of diazomethane in ether until all of the acid dissolvesand a yellow color persists. Evaporate the solvents and crystallize theresidue from toluene-hexane to obtain the title compound, m.p.114°-116°.

Although the instant invention has been described in the foregoingspecification in terms of the use of the novel oxathiepins disclosedherein in the treatment and control of human and warm-blooded animaldisease conditions characterized by excessive undesirable contractileactivity of prostaglandins and prostaglandin biosynthetic intermediates,and particularly of asthma, it will be recognized by those skilled inthe art that, in addition to the involvement of contractileprostaglandins in chronic obstructive lung disease (e.g. asthma),prostaglandins play a role in other allergic conditions as well as ininflammation, diarrhea, hypertension, angina, platelet aggregation,cerebral spasm, premature abortion and dismenorrhea. Also theoxathiepins of this invention are potent TXA₂ biosynthesis inhibitors,inhibiting platelet aggregation, and can be useful in diseases such asatherosclerosis, and myocardial infarction. Applicants considerapplication of the oxathiepins disclosed and claimed herein to thetreatment and control of such disease conditions to be obviousequivalents to the invention as disclosed by applicants and to fallwithin the scope of the instant invention.

Certain of the compounds of the present invention can be separated intooptically active (+) and (-) isomers. In such cases, the presentinvention includes both the racemic as well as the resolved forms of thecompound, simply by naming the compound itself.

The subject matter which applicants regard as their invention, and whichis sought to be patented herein, is particularly pointed out anddistinctly claimed as follows.

What is claimed is:
 1. A compound selected from the group consisting of6H-dibenz[b,e][1,4]oxathiepins having the structural formulae: ##STR24##wherein Z is a member selected from the group consisting of thio,sulfinyl, and sulfonyl; R₂ and R₃ are the same or different and aremembers selected from the group consisting of hydrogen, halogen, nitro,loweralkyl, amino, N-loweralkylamino, N,N-diloweralkylamino,loweralkanoyl, hydroxy, loweralkoxy, loweralkylthio,trifluoromethylthio, loweralkylsulfinyl, loweralkylsulfonyl, andtrifluoromethyl; and R₁ is 3-hydroxy-1,2,5-thiadiazol-4-yl; and thepharmaceutically acceptable salt thereof.
 2. A compound of claim 1having the name;2-(3-Hydroxy-1,2,5-thiadiazol-4-yl)-6H-dibenz[b,e][1,4]oxathiepin.
 3. Acompound of claim 1, wherein Z is thio.
 4. A compound of claim 1,wherein Z is thio; R₂ is selected from hydrogen, amino, nitro or fluoro;R₃ is hydrogen.
 5. A compound of claim 4, wherein R₂ is hydrogen.
 6. Acompound of claim 1, wherein Z is sulfinyl; R₂ is selected fromhydrogen, amino, nitro or fluoro; R₃ is hydrogen.
 7. A compound of claim6, wherein R₂ is hydrogen.
 8. A compound of claim 1, wherein Z issulfonyl; R₂ is selected from hydrogen, amino, nitro or fluoro; R₃ ishydrogen.
 9. A compound of claim 8, wherein R₂ is hydrogen.